Distinct intracellular domain substrate modifications selectively regulate ectodomain cleavage of NRG1 or CD44

Molecular and Cellular Biology

Volumn 35, Issue 19, 2015, Pages 3381-3395

  Parra, Liseth M ^a,b   Hartmann, Monika ^a   Schubach, Salome ^a   Li, Yong ^a,c   Herrlich, Peter ^a   Herrlich, Andreas ^b  

^a FRITZ LIPMANN INSTITUTE   (Germany)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c ANHUI UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

CHIMERIC PROTEIN; HERMES ANTIGEN; NEU DIFFERENTIATION FACTOR; PHORBOL 13 ACETATE 12 MYRISTATE; PROTEIN KINASE C DELTA; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME; CD44 PROTEIN, MOUSE; NRG1 PROTEIN, MOUSE; PRKCD PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL MIGRATION; CONTROLLED STUDY; DEPHOSPHORYLATION; DOWN REGULATION; EMBRYO; EX VIVO STUDY; HUMAN; HUMAN CELL; IN VIVO STUDY; MOUSE; MYELINATION; NERVE FIBER; NERVE FIBER GROWTH; NONHUMAN; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN MODIFICATION; PROTEIN PHOSPHORYLATION; PROTEIN SECRETION; TRIGEMINUS GANGLION; AMINO ACID SEQUENCE; CHEMISTRY; COCULTURE; CYTOLOGY; HEK293 CELL LINE; METABOLISM; MOLECULAR GENETICS; NEURITE; PHOSPHORYLATION; PHYSIOLOGY; PROTEIN PROCESSING; SCHWANN CELL; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANTIGENS, CD44; COCULTURE TECHNIQUES; HEK293 CELLS; HUMANS; MOLECULAR SEQUENCE DATA; NEUREGULIN-1; NEURITES; PHOSPHORYLATION; PROTEIN KINASE C-DELTA; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEOLYSIS; SCHWANN CELLS; SIGNAL TRANSDUCTION; TRIGEMINAL GANGLION;

EID: 84941051404     PISSN: 02707306     EISSN: 10985549     Source Type: Journal    
DOI: 10.1128/MCB.00500-15     Document Type: Article

References (67)

1. Dreymueller D, Pruessmeyer J, Groth E, Ludwig A. 2011. The role of ADAM-mediated shedding in vascular biology. Eur J Cell Biol 91:472-485. http://dx.doi.org/10.1016/j.ejcb.2011.09.003.
2. Hartmann M, Herrlich A, Herrlich P. 2013. Who decides when to cleave an ectodomain? Trends Biochem Sci 38:111-120. http://dx.doi.org/10.1016/j.tibs.2012.12.002.
3. Montes de Oca-B P. 2010. Ectdomain shedding and regulated intracellular proteolysis in the central nervous system. Cent Nerv Syst Agents Med Chem 10:337-359. http://dx.doi.org/10.2174/187152410793429700.
4. Hartmann M, Parra LM, Ruschel A, Schubert S, Li Y, Morrison H, Herrlich A, Herrlich P. 2015. Tumor suppressor NF2 blocks cellular migration by inhibiting ectodomain cleavage of CD44. Mol Cancer Res 13:879-890. http://dx.doi.org/10.1158/1541-7786.MCR-15-0020-T.
5. Dang M, Armbruster N, Miller MA, Cermeno E, Hartmann M, Bell GW, Root DE, Lauffenburger DA, Lodish HF, Herrlich A. 2013. Regulated ADAM17-dependent EGF family ligand release by substrateselecting signaling pathways. Proc Natl Acad Sci U S A 110:9776-9781. http://dx.doi.org/10.1073/pnas.1307478110.
6. Fleck D, van Bebber F, Colombo A, Galante C, Schwenk BM, Rabe L, Hampel H, Novak B, Kremmer E, Tahirovic S, Edbauer D, Lichtenthaler SF, Schmid B, Willem M, Haass C. 2013. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci 33:7856-7869. http://dx.doi.org/10.1523/JNEUROSCI.3372-12.2013.
7. Newbern J, Birchmeier C. 2010. Nrg1/ErbB signaling networks in Schwann cell development and myelination. Semin Cell Dev Biol 21:922-928. http://dx.doi.org/10.1016/j.semcdb.2010.08.008.
8. Nave KA, Salzer JL. 2006. Axonal regulation of myelination by neuregulin 1. Curr Opin Neurobiol 16:492-500. http://dx.doi.org/10.1016/j.conb.2006.08.008.
9. Liu FF, Stone JR, Schuldt AJ, Okoshi K, Okoshi MP, Nakayama M, Ho KK, Manning WJ, Marchionni MA, Lorell BH, Morgan JP, Yan X. 2005. Heterozygous knockout of the neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. Am J Physiol Heart Circ Physiol 289: H660-H666. http://dx.doi.org/10.1152/ajpheart.00268.2005.
10. Jin H, Sperka T, Herrlich P, Morrison H. 2006. Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature 442:576-579. http://dx.doi.org/10.1038/nature04856.
11. Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, Seluanov A. 2013. High-molecularmass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499:346-349. http://dx.doi.org/10.1038/nature12234.
12. Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA, Gutmann DH, Ponta H, Herrlich P. 2001. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev 15:968-980. http://dx.doi.org/10.1101/gad.189601.
13. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. 2003. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983-3988. http://dx.doi.org/10.1073/pnas.0530291100.
14. + prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25:1696-1708. http://dx.doi.org/10.1038/sj.onc.1209327.
15. Pietras A, Katz AM, Ekström EJ, Wee B, Halliday JJ, Pitter KL, Werbeck JL, Amankulor NM, Huse JT, Holland EC. 2014. Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14:357-369. http://dx.doi.org/10.1016/j.stem.2014.01.005.
16. Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, Apuzzo T, Sperduti I, Volpe S, Cocorullo G, Gulotta G, Dieli F, De Maria R, Stassi G. 2014. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14:342-356. http://dx.doi.org/10.1016/j.stem.2014.01.009.
17. Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, Liu A, Miu K, Watnick RS, Reinhardt F, McAllister SS, Jacks T, Weinberg RA. 2008. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134:62-73. http://dx.doi.org/10.1016/j.cell.2008.06.006.
18. Matzke A, Herrlich P, Ponta H, Orian-Rousseau V. 2005. A five-aminoacid peptide blocks Met-and Ron-dependent cell migration. Cancer Res 65:6105-6110. http://dx.doi.org/10.1158/0008-5472.CAN-05-0207.
19. Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. 1991. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65:13-24. http://dx.doi.org/10.1016/0092-8674(91)90403-L.
20. Yu Q, Toole BP, Stamenkovic I. 1997. Induction of apoptosis of metastatic mammary carcinoma cells in vivo by disruption of tumor cell surface CD44 function. J Exp Med 186:1985-1996. http://dx.doi.org/10.1084/jem.186.12.1985.
21. Zeilstra J, Joosten SPJ, van Andel H, Tolg C, Berns A, Snoek M, van de Wetering M, Spaargaren M, Clevers H, Pals ST. 2014. Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling. Oncogene 33:665-670. http://dx.doi.org/10.1038/onc.2012.611.
22. Sherman L, Wainwright D, Ponta H, Herrlich P. 1998. A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth. Genes Dev 12:1058-1071. http://dx.doi.org/10.1101/gad.12.7.1058.
23. Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H. 2002. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16:3074-3086. http://dx.doi.org/10.1101/gad.242602.
24. Lautrette A, Li S, Alili R, Sunnarborg SW, Burtin M, Lee DC, Friedlander G, Terzi F. 2005. Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nat Med 11:867-874. http://dx.doi.org/10.1038/nm1275.
25. Sternlicht MD, Sunnarborg SW. 2008. The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. J Mammary Gland Biol Neoplasia 13:181-194. http://dx.doi.org/10.1007/s10911-008-9084-6.
26. Perugorria MJ, Latasa MU, Nicou A, Cartagena-Lirola H, Castillo J, Goñi S, Vespasiani-Gentilucci U, Zagami MG, Lotersztajn S, Prieto J, Berasain C, Avila MA. 2008. The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology 48:1251-1261. http://dx.doi.org/10.1002/hep.22437.
27. Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, Adachi S, Kitakaze M, Hashimoto K, Raab G, Nanba D, Higashiyama S, Hori M, Klagsbrun M, Mekada E. 2003. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci U S A 100:3221-3226. http://dx.doi.org/10.1073/pnas.0537588100.
28. Kveiborg M, Instrell R, Rowlands C, Howell M, Parker PJ. 2011. PKCα and PKCδ regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways. PLoS One 6:e17168. http://dx.doi.org/10.1371/journal.pone.0017168.
29. Dang M, Dubbin K, D'Aiello A, Hartmann M, Lodish H, Herrlich A. 2011. Epidermal growth factor (EGF) ligand release by substrate-specific a disintegrin and metalloproteases (ADAMs) involves different protein kinase C (PKC) isoenzymes depending on the stimulus. J Biol Chem 286: 17704-17713. http://dx.doi.org/10.1074/jbc. M110.187823.
30. Le Gall SM, Maretzky T, Issuree PDA, Niu X-D, Reiss K, Saftig P, Khokha R, Lundell D, Blobel CP. 2010. ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site. J Cell Sci 123:3913-3922. http://dx.doi.org/10.1242/jcs.069997.
31. Düsterhöft S, Höbel K, Oldefest M, Lokau J, Waetzig GH, Chalaris A, Garbers C, Scheller J, Rose-John S, Lorenzen I, Grötzinger J. 2014. A disintegrin and metalloprotease 17 dynamic interaction sequence, the sweet tooth for the human interleukin 6 receptor. J Biol Chem 289:16336-16348. http://dx.doi.org/10.1074/jbc. M114.557322.
32. Düsterhöft S, Jung S, Hung C-W, Tholey A, Sonnichsen FD, Grötzinger J, Lorenzen I. 2013. Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase. J Am Chem Soc 135:5776-5781. http://dx.doi.org/10.1021/ja400340u.
33. Willems SH, Tape CJ, Stanley PL, Taylor NA, Mills IG, Neal DE, McCafferty J, Murphy G. 2010. Thiol isomerases negatively regulate the cellular shedding activity of ADAM17. Biochem J 428:439-450. http://dx.doi.org/10.1042/BJ20100179.
34. Xu P, Liu J, Sakaki-Yumoto M, Derynck R. 2012. TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal 5:ra34. http://dx.doi.org/10.1126/scisignal.2002689.
35. Xu P, Derynck R. 2010. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell 37:551-566. http://dx.doi.org/10.1016/j.molcel.2010.01.034.
36. Herrlich A, Klinman E, Fu J, Sadegh C, Lodish H. 2008. Ectodomain cleavage of the EGF ligands HB-EGF, neuregulin1-beta, and TGF-alpha is specifically triggered by different stimuli and involves different PKC isoenzymes. FASEB J 22:4281-4295. http://dx.doi.org/10.1096/fj.08-113852.
37. Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP. 2004. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164: 769-779. http://dx.doi.org/10.1083/jcb.200307137.
38. Parra LM, Zou Y. 2010. Sonic hedgehog induces response of commissural axons to semaphorin repulsion during midline crossing. Nat Neurosci 13:29-35. http://dx.doi.org/10.1038/nn.2457.
39. Lillesaar C, Fried K. 2004. Neurites from trigeminal ganglion explants grown in vitro are repelled or attracted by tooth-related tissues depending on developmental stage. Neuroscience 125:149-161. http://dx.doi.org/10.1016/j.neuroscience.2004.01.008.
40. Torres-Espín A, Santos D, González-Pérez F, Del Valle J, Navarro X. 2014. Neurite-J: an Image-J plug-in for axonal growth analysis in organotypic cultures. J Neurosci methods 236:26-39. http://dx.doi.org/10.1016/j.jneumeth.2014.08.005.
41. Hartmann M, Parra LM, Ruschel A, Lindner C, Morrison H, Herrlich A, Herrlich P. 2015. Inside-out regulation of ectodomain cleavage of cluster-of-differentiation-44 (CD44) and of neuregulin-1 requires substrate dimerization. J Biol Chem 290:17041-17054. http://dx.doi.org/10.1074/jbc. M114.610204.
42. Bollen M, Peti W, Ragusa MJ, Beullens M. 2010. The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci 35:450-458. http://dx.doi.org/10.1016/j.tibs.2010.03.002.
43. Mori T, Kitano K, Terawaki S-I, Maesaki R, Fukami Y, Hakoshima T. 2008. Structural basis for CD44 recognition byERMproteins. J Biol Chem 283:29602-29612. http://dx.doi.org/10.1074/jbc. M803606200.
44. Fricker FR, Antunes-Martins A, Galino J, Paramsothy R, La Russa F, Perkins J, Goldberg R, BrelstaffJ, Zhu N, McMahon SB, Orengo C, Garratt AN, Birchmeier C, Bennett DLH. 2013. Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination. Brain 136: 2279-2297. http://dx.doi.org/10.1093/brain/awt148.
45. Meyer D, Yamaai T, Garratt A, Riethmacher-Sonnenberg E, Kane D, Theill LE, Birchmeier C. 1997. Isoform-specific expression and function of neuregulin. Development 124:3575-3586.
46. Birchmeier C, Nave K-A. 2008. Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia 56:1491-1497. http://dx.doi.org/10.1002/glia.20753.
47. Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Müller T, Wende H, Stassart RM, Nawaz S, Humml C, Velanac V, Radyushkin K, Goebbels S, Fischer TM, Franklin RJ, Lai C, Ehrenreich H, Birchmeier C, Schwab MH, Nave KA. 2008. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59:581-595. http://dx.doi.org/10.1016/j.neuron.2008.06.028.
48. Liu X, Hwang H, Cao L, Buckland M, Cunningham A, Chen J, Chien KR, Graham RM, Zhou M. 1998. Domain-specific gene disruption reveals critical regulation of neuregulin signaling by its cytoplasmic tail. Proc Natl Acad Sci U S A 95:13024-13029. http://dx.doi.org/10.1073/pnas.95.22.13024.
49. Liu X, Hwang H, Cao L, Wen D, Liu N, Graham RM, Zhou M. 1998. Release of the neuregulin functional polypeptide requires its cytoplasmic tail. J Biol Chem 273:34335-34340. http://dx.doi.org/10.1074/jbc.273.51.34335.
50. Esper RM, Loeb JA. 2009. Neurotrophins induce neuregulin release through protein kinaseCδ activation. J Biol Chem 284:26251-26260. http://dx.doi.org/10.1074/jbc. M109.002915.
51. Kahn J, Walcheck B, Migaki GI, Jutila MA, Kishimoto TK. 1998. Calmodulin regulates L-selectin adhesion molecule expression and function through a protease-dependent mechanism. Cell 92:809-818. http://dx.doi.org/10.1016/S0092-8674(00)81408-7.
52. Matala E, Alexander SR, Kishimoto TK, Walcheck B. 2001. The cytoplasmic domain of L-selectin participates in regulating L-selectin endoproteolysis. J Immunol 167:1617-1623. http://dx.doi.org/10.4049/jimmunol.167.3.1617.
53. Killock DJ, Ivetić A. 2010. The cytoplasmic domains of TNFα-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding. Biochem J 428:293-304. http://dx.doi.org/10.1042/BJ20091611.
54. Darmellah A, Rayah A, Auger R, Cuif M-H, Prigent M, Arpin M, Alcover A, Delarasse C, Kanellopoulos JM. 2012. Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein. J Biol Chem 287:34583-34595. http://dx.doi.org/10.1074/jbc. M112.400010.
55. Kohlstedt K, Shoghi F, Müller-Esterl W, Busse R, Fleming I. 2002. CK2 phosphorylates the angiotensin-converting enzyme and regulates its retention in the endothelial cell plasma membrane. Circ Res 91:749-756. http://dx.doi.org/10.1161/01.RES.0000038114.17939.C8.
56. Müllberg J, Oberthür W, Lottspeich F, Mehl E, Dittrich E, Graeve L, Heinrich PC, Rose-John S. 1994. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol 152: 4958-4968.
57. Crowe PD, VanArsdale TL, Goodwin RG, Ware CF. 1993. Specific induction of 80-kDa tumor necrosis factor receptor shedding in T lymphocytes involves the cytoplasmic domain and phosphorylation. J Immunol 151:6882-6890.
58. Wang X, Mizushima H, Adachi S, Ohishi M, Iwamoto R, Mekada E. 2006. Cytoplasmic domain phosphorylation of heparin-binding EGF-like growth factor. Cell Struct Funct 31:15-27. http://dx.doi.org/10.1247/csf.31.15.
59. Maretzky T, Evers A, Le Gall S, Alabi RO, Speck N, Reiss K, Blobel CP. 2015. The cytoplasmic domain of a disintegrin and metalloproteinase 10 (ADAM10) regulates its constitutive activity but is dispensable for stimulated ADAM10-dependent shedding. J Biol Chem 290:7416-7425. http://dx.doi.org/10.1074/jbc. M114.603753.
60. Schwarz J, Broder C, Helmstetter A, Schmidt S, Yan I, Müller M, Schmidt-Arras D, Becker-Pauly C, Koch-Nolte F, Mittrücker H-W, Rabe B, Rose-John S, Chalaris A. 2013. Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17. Biochim Biophys Acta 1833:3355-3367. http://dx.doi.org/10.1016/j.bbamcr.2013.10.005.
61. Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA. 2000. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275:14608-14614. http://dx.doi.org/10.1074/jbc.275.19.14608.
62. Maretzky T, McIlwain DR, Issuree PDA, Li X, Malapeira J, Amin S, Lang PA, Mak TW, Blobel CP. 2013. iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding. Proc Natl Acad Sci U S A 110:11433-11438. http://dx.doi.org/10.1073/pnas.1302553110.
63. Tsukamoto H, Tanida S, Ozeki K, Ebi M, Mizoshita T, Shimura T, Mori Y, Kataoka H, Kamiya T, Fukuda S, Higashiyama S, Joh T. 2013. Annexin A2 regulates a disintegrin and metalloproteinase 17-mediated ectodomain shedding of pro-tumor necrosis factor-α in monocytes and colon epithelial cells. Inflamm Bowel Dis 19:1365-1373. http://dx.doi.org/10.1097/MIB.0b013e318281f43a.
64. Nakayama H, Fukuda S, Inoue H, Nishida-Fukuda H, Shirakata Y, Hashimoto K, Higashiyama S. 2012. Cell surface annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin. Mol Biol Cell 23:1964-1975. http://dx.doi.org/10.1091/mbc. E11-08-0683.
65. Legg JW, Lewis CA, Parsons M, Ng T, Isacke CM. 2002. A novel PKCregulated mechanism controls CD44 ezrin association and directional cell motility. Nat Cell Biol 4:399-407. http://dx.doi.org/10.1038/ncb797.
66. Fridman JS, Caulder E, Hansbury M, Liu X, Yang G, Wang Q, Lo Y, Zhou BB, Pan M, Thomas SM, Grandis JR, Zhuo J, Yao W, Newton RC, Friedman SM, Scherle PA, Vaddi K. 2007. Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res 13:1892-1902. http://dx.doi.org/10.1158/1078-0432.CCR-06-2116.
67. Friedman S, Levy R, Garrett W, Doval D, Bondarde S, Sahoo T, Lokanatha D, Julka P, Shenoy K, Nagarkar R, Bhattacharyya G, Kumar K, Nag S, Mohan P, Narang N, Raghunadharao D, Walia M, Yao W, Li J, Emm T, Yeleswaram S, Scherle P, Newton R. 2009. Clinical benefit of INCB7839, a potent and selective inhibitor of ADAM10 and ADAM17, in combination with trastuzumab in metastatic HER2-positive breast cancer patients. Cancer Res 69(Suppl):5056.